Respiratory Syncytial Virus (“RSV”) is the most important respiratory pathogen in infancy and early childhood. Studies estimate that RSV causes up to 90% of brochiolitis and approximately 90% of all pneumonia in infancy. These conditions result in over 90,000 hospitalizations and 4500 deaths annually in the United States alone (Hall, 1998, Textbook of Pediatric Infectious Diseases, 2084-2111). RSV infection in early childhood might be an important risk factor for subsequent development of recurrent wheezing and asthma (Eigen, 1999, J. Pediatr. 135:S1-S50; Stein et al., 1999, Lancet 354:541-545).
Current methods for treatment and prevention of RSV infection are limited. For instance, vaccination against RSV has not been successful to date. Vaccination of infants with an inactivated RSV actually increased the severity of RSV infection and pulmonary pathology when vaccinated infants were later challenged with RSV (Groothius, 1994, Antiviral Res 23:1-10; Hall et al., 1995, Principles and Practice of Infectious Disease, 1501-1519; Wyde, 1998, Antiviral Res. 39:63-79).
Direct administration of antibodies against RSV has had some prophylactic effect. A human immunoglobulin against RSV (“RSVIG”) was approved in 1996 for the prevention of serious lower respiratory tract disease caused by RSV in premature infants and infants with bronchopulmonary dysplasia (PREVENT study group, 1999, Pediatrics 99:93-99). Recently, Synagis (or palivizumab), a humanized monoclonal antibody against the surface fusion glycoprotein (“F protein”) of RSV, was approved for similar indications (Meissner et al., 1999, Pediatrics 18:223-31; Johnson et al., 1997, J. Infect. Dis. 176:1215-1224; Impact-RSV Study Group, 1998, Pediatrics 102:531-537). In studies on test animals, Synagis was twice as potent as RSVIG in inhibiting the RSV-induced potentiation of inflammation when administered before or in the early phase of RSV infection (Piedimonte et al., 2000, Pediatric Research 47:351-356).
Although Synagis provides safe and effective prevention of RSV infection, improved therapeutics, such as small molecule therapeutics, are needed to treat and/or prevent RSV infection. Small molecule therapeutics are easier and less expensive to manufacture and also easier to administer orally. In addition, a small molecule therapeutic such as an antigen that mimics the epitope recognized by Synagis could be administered to generate an immune response against RSV. A composition comprising an antigen that mimics RSV would provide a safer method of preventing RSV infection. An effective antigen mimic of RSV could be administered, to persons with a functioning immune system, as an immunoprophylactic to raise an immune response against the virus with minimal or no danger of infection caused by the immunoprophylactic itself.
The three-dimensional structure coordinates of crystalline Synagis would enable the design or selection of such an antigen mimic. Synagis is effective in preventing RSV infection in vivo, and a mimic of an antigen bound specifically by Synagis could raise an immune response that is as effective or even more effective than Synagis in preventing infection. The structure coordinates of the antigen binding region of crystalline Synagis and/or the structure coordinates of a co-crystal complex of Synagis and an antigen would elucidate the atomic requirements of binding between Synagis and the antigen. This atomic resolution information could then be used to design and/or select a mimic of the antigen to be used as an immunoprophylactic against RSV.
Furthermore, the atomic structure coordinates of crystalline Synagis would enable the design of an antibody with improved virus binding and/or neutralizing properties. The atomic structure coordinates of crystalline Synagis would identify those residues of Synagis that are involved in antigen-antibody binding. These residues could then be selectively altered to generate mutant Synagis molecules that could be screened for binding and/or virus neutralizing effects. These improved Synagis molecules would provide more and perhaps improved options for prevention of RSV infection.
Until the present invention, the ability to obtain the atomic structure coordinates of Synagis has not been realized.